NK cells are needed in the body to kill virus infected cells. NK-mediated virus immunity has been linked with innate cytokines (e.g. type I interferons), sustained dendritic cells and accelerated acquisition of virus specific effector T cells in infected animals. However, little is known about how efficient NK-mediated virus immunity can regulate and shape maturation and/or activation profiles of other immune cells. This proposal is based on a new genetic model for NK-mediated virus immunity under MHC control in two recombinant congenic strains of mice referred to as R2 and R7. R2 and R7 only differ by ~300-kb in the MHC class I D subregion, but NK-mediated virus immunity is remarkable in R7 mice. The broad long-term objective for this research project seeks to examine how efficient NK-mediated virus immunity can impart dramatic control over immune cells, in addition to their critical function in innate immunity, through controlled genetic comparisons. A guiding hypothesis is that NK-mediated virus control differences in R2 and R7 will be linked with induction of adaptive immunity through regulation of a fine balance of cytokines before virus levels differ significantly.
Three specific aims are proposed:
Aim 1. To determine the effect of MHC regulated NK cell function on the induction and kinetics of the CD8+ T cell response to MCMV infection. CD8+ CTLs from R2 and R7 will be assessed in flow cytometric and cytotoxicity assays to ascertain the induction time course, response magnitude, activation state and effector activity after infection. Adoptive transfers with CD8+ TCR transgenic T-cells will further define the induction and the effector activity CDS T cells responding in the spleens of resistant and susceptible mice.
Aim 2. To analyze the effect of NK cell-DC interactions on splenic NK cell function. Activation states for splenic NK cells and the frequency and subset distribution of CDllc+ DCs after infection of R2 and R7 will be analyzed using flow cytometry. Splenic cytokine production, especially type 1 interferon and IL-10, will be evaluated via multiplex cytokine assays.
Aim 3. To examine a potential causal role for IL-10 underlying MHC regulated differences in NK cell-mediated virus immunity. A potential regulatory role for IL-10 on the induction of adaptive immunity will be evaluated in IL10GFP knock-in reporter mice and IL-10 deficient mice

Public Health Relevance

Natural killer (NK) cells are needed in the body to fight against viruses by killing infected cells. The central focus for this research proposal is to investigate how NK cells sustain and enhance the role of other immune cells, especially dendritic cells and T cells, which are also needed to provide antiviral immune responses and very specific killing of virus infected cells.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-BDP-I)
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University of Virginia
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Labonte, Adam C; Sung, Sun-Sang J; Jennelle, Lucas T et al. (2017) Expression of scavenger receptor-AI promotes alternative activation of murine macrophages to limit hepatic inflammation and fibrosis. Hepatology 65:32-43
Sung, Sun-Sang J; Ge, Yan; Dai, Chao et al. (2017) Dependence of Glomerulonephritis Induction on Novel Intraglomerular Alternatively Activated Bone Marrow-Derived Macrophages and Mac-1 and PD-L1 in Lupus-Prone NZM2328 Mice. J Immunol 198:2589-2601
Jiang, Li; Yao, Shuyu; Huang, Su et al. (2016) Type I IFN signaling facilitates the development of IL-10-producing effector CD8+ T cells during murine influenza virus infection. Eur J Immunol 46:2778-2788
Teoh, Jeffrey J; Gamache, Awndre E; Gillespie, Alyssa L et al. (2016) Acute Virus Control Mediated by Licensed NK Cells Sets Primary CD8+ T Cell Dependence on CD27 Costimulation. J Immunol 197:4360-4370
Tosello-Trampont, Annie-Carole; Krueger, Peter; Narayanan, Sowmya et al. (2016) NKp46(+) natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice. Hepatology 63:799-812
DeBerge, Matthew P; Ely, Kenneth H; Wright, Peter F et al. (2015) Shedding of TNF receptor 2 by effector CD8? T cells by ADAM17 is important for regulating TNF-? availability during influenza infection. J Leukoc Biol 98:423-34
Krueger, Peter D; Kim, Taeg S; Sung, Sun-Sang J et al. (2015) Liver-resident CD103+ dendritic cells prime antiviral CD8+ T cells in situ. J Immunol 194:3213-22
Moser, Emily K; Sun, Jie; Kim, Taeg S et al. (2015) IL-21R signaling suppresses IL-17+ gamma delta T cell responses and production of IL-17 related cytokines in the lung at steady state and after Influenza A virus infection. PLoS One 10:e0120169
Ramana, Chilakamarti V; DeBerge, Matthew P; Kumar, Aseem et al. (2015) Inflammatory impact of IFN-? in CD8+ T cell-mediated lung injury is mediated by both Stat1-dependent and -independent pathways. Am J Physiol Lung Cell Mol Physiol 308:L650-7
Kim, Taeg S; Hanak, Mark; Trampont, Paul C et al. (2015) Stress-associated erythropoiesis initiation is regulated by type 1 conventional dendritic cells. J Clin Invest 125:3965-80

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